Despite recent improvements in mortality, cardiovascular diseases (heart attacks and strokes) remain the leading causes of death. Cardiovascular disease events are triggered by platelet aggregation. Beyond platelet aggregation, there is accumulating evidence that platelet secretion activates pro-thrombotic and pro-inflammatory pathways that cause acute thrombotic occlusion, mediate vascular remodeling and accelerate the atherosclerotic process. Unfortunately, there are no medications available to block the secretory process. Recently we and others have begun to elucidate the molecular mechanisms of platelet secretion. This proposal seeks to translate these molecular insights into experiments in vivo, that examine the novel hypothesis that platelet secretion could be a therapeutic target for preventing acute thrombotic arterial occlusion, arteriosclerotic vascular remodeling, atherosclerotic plaque rupture and the progression of atherosclerosis. We have selected two key molecular targets in the platelet secretory process. The first target is Rab geranylgeranyltransferase (RabGGTase), an enzyme downstream of the cholesterol biosynthesis pathway, which mediates the formation of platelet alpha granules that secrete pro-thrombotic and pro-inflammatory molecules (e.g., P-selectin, CD40L, etc.). The second target is HPS3p which plays an integral, selective role in the formation of platelet dense granules which contain ADP and other platelet activating molecules. Genetically altered mice deficient in RabGGTase or HPS3p will be used to determine how defects in alpha and/or dense granule secretion affect 1) the release of P-selectin, CD40L and other pro-inflammatory and pro-thrombotic molecules; 2) platelet aggregation; 3) thrombotic occlusion and vascular remodeling following acute vascular injury and, 4) the rates of plaque rupture and the progression of vascular lesions in ApoE-/- atherosclerotic mice. These experiments should define whether targeting these molecules to inhibit the platelet alpha and/or dense granule secretion could be an effective therapeutic strategy for reducing cardiovascular disease.